Tapentadol, 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol) is a centrally acting analgesic with a dual mode of action: mu-opioid receptor agonism and noradrenaline reuptake inhibition. Its dual mode of action provides analgesia at similar levels of more potent narcotic analgesics such as hydrocodone, oxycodone, and morphine with a more tolerable side effect profile. Tapentadol was first disclosed and claimed in European patent no. EP 693,475, US. Pat. No. 6,248,737 and US. Pat. RE39,593. The immediate release pharmaceutical composition of tapentadol is the subject of the United States Food and Drug Administration Approved New Drug Application number 22-304.
There are a number of classes of analgesic compounds used for treating acute and chronic pain. These include acetaminophen, NSAIDs such as naproxen, meloxicam etc, CINODS such as naproxcinod, OPIATES such as morphine, tramadol, tapentadol, oxycodone etc, GABA analogues such as pregabalin and SNRIs such as duloxetine etc.
Pregabalin, a GABA analogue, is an anticonvulsant drug used for neuropathic pain, as an adjunct therapy for partial seizures, and in generalized anxiety disorder. Pregabalin was designed as a more potent successor to gabapentin and it is marketed by Pfizer under the trade name Lyrica®. In general, pregabalin reduces the release of several neurotransmitters, including glutamate, noradrenaline, and substance P. Gabapentin is another GABA analogue similar to Pregabalin and was initially synthesized to mimic the chemical structure of the neurotransmitter gamma-aminobutyric acid (GABA), but is not believed to act on the same brain receptors. Its exact mechanism of action is unknown, but its therapeutic action on neuropathic pain is thought to involve voltage-gated N-type calcium ion channels. It is thought to bind to the α2δ subunit of the voltage-dependent calcium channel in the central nervous system.
NSAIDs non-steroidal anti-inflammatory drug (NSAIDs) include but are not limited to Diclofenac; Celecoxib; Diflunisal; Etodolac; Fenoprofen; Ibuprofen; Indomethacin; Ketoprofen, and, Ketorolac and used for treating pain.
Serotonin Norepinephrine Reuptake inhibitors (SNRIs) are a class of antidepressant used in the treatment of clinical depression, anxiety disorders, obsessive-compulsive disorder, attention deficit hyperactivity disorder (ADHD) and chronic neuropathic pain. They act upon two neurotransmitters in the brain that are known to play an important part in mood, namely, serotonin and norepinephrine. Examples of SNRIs include Venlafaxine, duloxetine, milnacipran and desvenlafaxine etc.
The drugs acting on 5-HT receptors are usually designated as 5-HTagonists. The 5 HT1 agonists are known and used for the treatment of headaches including migraine headache. They were first introduced in the 1990s. While effective at treating individual headaches, they are neither a preventative nor a cure. Triptans include sumatriptan, (Imitrex, Imigran), rizatriptan (Maxalt), naratriptan (Amerge, Naramig), zolmitriptan (Zomig), eletriptan (Relpax), almotriptan (Axert, Almogran), and frovatriptan (Frova, Migard).
Cyclo-oxygenase-(COX)-inhibiting nitric oxide donator or “CINODs” have a nitric oxide (NO)-releasing group and are also designated No-NSAIDs. These include but not limited to naproxcinod among others.
Proton Pump Inhibitors (“PPI”s) are a group of drugs that produce pronounced and long-lasting reduction of gastric acid production. PPIs structurally are usually benzimidazole and benzimidazole—like derivatives. The key PPIs include Clinically used proton pump inhibitors: Omeprazole (brand names: Losec, Prilosec, Zegerid, ocid), Lansoprazole (brand names: Prevacid, Zoton, Inhibitol), Esomeprazole (brand names: Nexium), Pantoprazole (FORMULA 15) (brand names: Protonix, Somac, Pantoloc, Pantozol, Zurcal, Pan),Rabeprazole (brand names: Rabecid, Aciphex, Pariet, Rabeloc. Dorafem:
Despite the benefits derived from these pain drugs, one area of concern relates to the incidence of unwanted side effects caused by these drugs. Thus there is an unmet need to develop pharmaceutical dosage forms comprising tapentadol such that the dosage forms with enhanced analgesic properties with as minimal side effects as possible. Hence it is desirable to develop dosage forms with reduced dosages of these drugs to alleviate the patients of its side effects without comprising the extent of pain relief.
The use of antagonist to address the potential side effects and the abuse are known in the art. Opioid antagonists are entities that modify the response of opioid receptors. Opioid antagonists include naloxone, naltrexone, diprenorphine, etorphine, dihydroetorphine, nalinefene, cyclazacine, levallorphan, pharmaceutically acceptable salts thereof and mixtures thereof.
For example, U.S. Pat. No. 5,866,164 describes a dosage system that comprises multiple layers with an opioid analgesic and the second layer comprises an antagonist for this opioid analgesic and simultaneously affecting the push function. U.S. Pat. No. 5,472,943 to Crain et al. describes methods of enhancing the analgesic potency of bimodally acting opioid agonists by administering the agonist with an opioid antagonist. U.S. Pat. No. 6,277,384 purported to provide a dosage form containing a combination of an opioid agonist and an opioid antagonist in a specific ratio, which brings about a negative effect on administration to an addicted person. U.S. Pat. No. 6,228,863 describes a dosage form containing a combination of an opioid agonist and an opioid antagonist, such that the two compounds can in each case only be extracted together from the dosage form and then additional processes required to separate them. U.S. Pat. No. 6,765,010 disclosures relate to compositions and methods with tramadol and an opioid antagonist to improve the efficacy of tramadol. U.S. Pat. Application No. 2005/0191244 describes the opioid agonist formulations comprising an opioid agonist, antagonist and gelling agent or an irritant to prevent the abuse opioid agonist. U.S. Pat. No. 6,716, 449 describes controlled release opioid agonist and controlled release opioid antagonist combinations for enhancing the analgesic potency of an opioid agonist and U.S. Pat. No. 7,332,142 describes pharmaceutical composition comprising an opioid agonist, an opioid antagonist and an irritant purport to lessen the abuse. U.S. Pat. No. 6,559,159 to Carroll et al. describes the use of kappa receptors antagonist for the treatment of opioid related addictions. U.S. Pat. No. 6,309,668 describes a tablet for oral administration containing two or more layers comprising one or more drugs and one or more gelling agents within separate layers of the tablet. U.S. Pat. No. 6,228,863 teaches the reduction of the abuse potential of oral dosage forms of opioid analgesics by selecting the particular opioid agonist and antagonist pair, and the concentrations of the same such that the antagonist cannot be easily extracted from the agonist. U.S. Pat. Nos. 6,277,384, 6,375,957 and 6,475,494 describe oral dosage forms including a combination of an orally active opioid agonist and an orally active opioid antagonist in a ratio that, when delivered orally, is analgesically effective but that is aversive in a physically dependent subject.
The prior art doesn't disclose a dosage form comprising at least one form of tapentadol and at least one opioid antagonist wherein the said tapentadol is in an optimal or suboptimal amount and the said antagonist is in amount effective to improve the efficacy and or reduce the side effects of tapentadol. Similarly, there is no report in the art of a method of treating pain by administering, to patient in need thereof, a dosage form comprising at least one form of tapentadol and at least one opioid antagonist wherein the said tapentadol is in an optimal or suboptimal amount and the said antagonist is in amount effective to improve the efficacy and or reduce the side effects of tapentadol. Similarly the prior art doesn't disclose a dosage form comprising at least one form of tapentadol and at least one opioid antagonist wherein the said tapentadol is in an optimal or suboptimal amount and the said antagonist is in amount effective to improve the efficacy and or reduce the side effects of tapentadol, such that the said dosage form provides effective pain relief for at least about 12 hours, or at least about 24 hours, when orally administered to a human patient.
Similarly, the prior art discloses neither a dosage form comprising at least one form of tapentadol and at least one opioid antagonist, and a therapeutically effective amount of a second analgesic wherein the said antagonist improves the efficacy and or reduces the side effects of tapentadol nor a method of treating pain and pain related conditions by administering to a patient in need thereof, a dosage forms comprising at least one form of tapentadol and at least one opioid antagonist wherein the said tapentadol is in an optimal or suboptimal amount and the said antagonist, and a therapeutically effective amount of a second drug wherein the said antagonist improves the efficacy and or reduces the side effects of tapentadol. The second analgesic is selected from a group consisting of an NSAID, Acetaminophen, a GABA analogue, a Serotonin Norepinephrine reuptake inhibitor (SNRI), a Cyclo-oxygenase-(COX)-inhibiting nitric oxide donator, a HT Agonist and a Proton Pump Inhibitor., tramadol, hydromorphone, faxeladol, axomadol, oxycodone, hydrocodone, fentanyl, morphine, pharmaceutically acceptable salts thereof and mixtures thereof.